Studies on the 4-anilinopiperidine class of analgesics have produced both clinically useful drugs and molecular probes for studying the opiate receptor. The goal of the present application is to develop improved compounds based on cis-beta-hydroxy-3-methylfentanyl, a relatively new and highly potent analog of fentanyl and cis-3-methylfentanyl. The specific aims are as follows: a) to separate the stereoisomers of cis-beta-hydroxy-3-methylfentanyl and determine the absolute stereochemistries of the most potent ones, b) to synthesize analogs of cis-beta-hydroxy-3-methylfentanyl in which systematic structural variations are made in different parts of the molecule, c) to obtain in vivo biological test data and to carry out in vitro ligand binding studies on six different opiate receptor subtypes (mu, delta(cx,) delta(ncx), kappa(l), kappa(2a), kappa(2b) on all compounds prepared, and d) to carry our detailed NMR analyses on all compounds prepared. The structural variations focus on the beta-hydroxy-beta-phenethyl portion of the molecule, the cis-3-methyl substituent, the 4-position of the piperidine ring, and the propionanilide portion of the molecule. Included among the structural variations are features which may reduce or eliminate respiratory depressant effects while maintaining analgesic potency. The knowledge derived from the proposed study will provide a broader understanding of the 4-anilinopiperidine class of analgesics. Such an understanding may translate into the development of potent analgesic agents devoid of adverse side effects such as respiratory depression and/or into the development of new treatment drugs and molecular probes for narcotic abuse.